Preeclampsia and cerebral palsy: are they related? Michael Collins' MD MS, Assistant Professor of Epidemiology; Nigel Paneth MD MPH, Professor of Pediatrics and Epidemiology; Department of Epidemiology and Department of Pediltrics and Human Development, College of Human Medicine, Michigan State University, A206 East Free Hall; East Lansing, hll48824-1316, USA.

'Correspondence to first atithot:

Were a patient to ask her obstetrician today, 'Will my preeclampsia increase the risk that my baby will dcvelop cue- bra1 palsy?', the answer would probably be yes. Eirene Collis et d.'s classic text1 on cerebral palsy (CP), for example, lists tox- emia of pregnancy first among factors which should prompt rleurological examination and follow-up of a neonate. But although preeclampsia (PE) and CP am both very familiar enti- ties to obstetricians and pediatricians, the links between the two have not frequently been investigated, and when they have, the results have been contradictory and confusing.

Both diagnoses suffer from lackof precision and standard- ization in practice. The diagnosis of PE is often applied clini- cally to any hypertensive gravida, including pregnant women with chronic essential hypertension, those with pregnancy- induccd hypertension (i.e. without protcinuria), and those with the combination of essential hypertension and PE'. Each of these conditions poses a different level of risk to the fetus, but the obstetrician seeing a patient for the tint time late in pregnancy cannot easily distinguish them.

Likewise, there is no diagnostic test for CP, and, although attempts have been made in recent years to standardize this diagnosis3, it is still based entirely on subjcctivc examination finding. Differences in the skill and experience of examiners surely play a role in the frequency with which the diagnosis is made, particularly in qilder cases. Another problem is the lack of agreement as to whether CP is an impairment, that is to say purely a finding on neurological examination, or a dis- ability, that is to say an entity causing measurable loss of clini- cally relevant motor functions.

Older studies attempting to link PE and CP generally focused on children of all birthweights, and tended to find either no association or a weak positive association between the two entities (Table I). But interest has been stimulated recently by several studies in very-low-birthweight (VLBW) infants that seem to find just the opposite, namely that PE is actually protective against CP (see Table I). At the same time, it has been demonstrated that certain brain abnormalities demonstrable by neonatal cranial ultrasound examination are strongly predictive of later CP in the VLBW infant'. This has encouraged investigators to view these ultrasonographic abnormalities as outcomes of interest themselves, interest- ing because they are diagnosed immediately, rather than a year or more after birth as is CE PE, in studies of these abnor-

\

b

malities, yields associations qualitatively similar to those found with CP; that is, PE appears to protett preterrn infants from such brain lesions (Table li). However, it is imponant to remember that there is not a one-to-one relation between ultrasound abnormalities and eventual CP

In three case-control studies among term or unselected infants, Gaffney et aL5, Blaia, and Dale and Stanley' each found elevated risks of CP when PE was present. By contract, in cohort studies, Palmer et al.* and Nelson and Ellenbergy, did not find significantly clevated risks of CP in the offspring o f preeclamptic mothers, although the latter study did find an elevated risk of CP when attention was restricted to moth- ers with severe proteinuria'".

.In contrast to the finding among term or unselected infants, two case-control studies"." of CP in low!birth- weight (LBW) infants, and five cohort studies withlultra- sound brain lesions as the depcndent ~ a r i a b l e ~ ) - ~ ~ ~ ~ ~ , found a decreased risk when PE was present. Two cohoni7-i9 and one case-control studyz0 of CF and three case-control studies of sonographic brain lesions in LBW all with somewhat lo!v power, reponed no protective effect. Two recent cohort studies of the effect of magnesium sulfate in VLBW infants contain data indicative of a protective effect of PE against CPZ4 and against sonographic lesionsz5.

Whatqan account for the difference in tindings between studies of the effect of PE in term or unselected infana and the findings in studies restricted to VLBW infant..? Could PE be causative of CP under some conditions, and protective under others?

Rationale for PE as a risk factor As has been known for some time, the strongest risk factor for the eventual development of CP is delivery of the fetus substantially before termz6. As all authorities on the treat- ment of PE agree that there is no cure forthis condition other than emptying the uterus, therapy of more severe or progres- sive casks of PE usually includes pretenn delivery.

In addition, true PE is a multisystem disease, character- . ized by derangement in a variety of normally homeostatic

systems, and characterized by widespread endothelial injury, alteration in the ratio of the vasoactive substances prostacy- f clin and thromboxane, and vascular hypersensitivity to pres- sor s u b s t a n ~ e s ~ ~ - 3 ~ . these changes are hypothesized to be

Deuelopnretitalhfedi~ne & CbiIdNetiroIogy 1998,40i 207-2 1 1 207

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secondary to an abnomially shallow invasion of the myome- trial vessels by trophoblast, resulting in a placental vascula- ture which remains responsive to vasnactive substances". This phenomenon, thought likely to occur on an immuno- logicai may represent the mother's partial 'rejec- tion' of an, jmmunoIogically foreign fetus3'. The consequent pathological syndrome, which leads to elevation of the maternal blood pressure, may be thought of as a fFtal demand for resources in the face of thk abnormal placenta-

& tionJ5. Thus some degree o f placentll ischemia occurs very early in the course of PE, even preceding clinical recognition of the condition. The known association of Pg with intrauterine growth retardation (IUGR) and fetal distress in labor supports the concept that PE causes a chronic ischemic environmeht for the developing fetus, which could plausibly result in the cerebral hemorrhagic, ischemic, or infarctive lesions which are reflected in the ultrasound abnormalities predictive ofCP

Rationale for PE as a protective factor The suggestion that PE may be protective against the devel- opment of CP in the preterm neonate is analogous to the theory>that the 'stress' of prolonged rupture of the fetal membranes may accelerate pulmonary maturity5GJ8. It has been similarly postulated that the stress of PE might accel-' erate fetal maturational processes generally, including those within the fetal brain". Since the preterm brain is more susceptible to brain lesions that are associated with CP, maturation shouldbe protective. From the evolutionary perspective, such mechanisms are neither unprecedented norimplausible. Larval amphibians accelerate their progress to metamorphosis in the presence of drying of their pond, and by analogy, in humans, selection might,have favored genes which promote fetal maturation in response to mes- sages of suboptimal intrauterine life. Though this general maturational effcct of PE seems plausible, it has not been supported by some recent s ~ d i e s ~ ~ ~ ' " . Kuban et al." suggest

prostaglandin effects as th; explanation of the protective effect of PE. lhey point out that the prostaglandin Idthrom- hoxane A, ratio is similar in PE to that created by treatment with indomcthacin, a therapy which in some hands has reduced the incidence of germinal matrix hemorrhage in preterm infants"'.

Methodological problems in the study of the PE/CP relation in LBW infants The possibility that gestational age (GA) may modify the action of PE Gpon the risk of CP is supported by the observa- tion that the cerebral pathology associated with CP is differ- ent in term and preterm infantsi2. But the paradox also suggests that bias may be occurring. Such bias could arise from several mechanisms which will now be discussed. (1) Earlydelivery is the strongest single predictor of CE This fact requires that if we have .an interest in the possibility of a direct effect of PE on thd likelihood ofCP (which would oper- ate regardless of the GA), we must control for GA. We would thus compare the risk ofCP in babies exposed to maternal PE with control babies ofsimilar GI\ whose mothers were free of PE. While this seems appropriate and even mdndatory, doing so by no means assures an appropriate comparison, for the following reasons: (a) Pretcrm delivery of babies from prceclamptic mothers is essentially iatrogenic in origin. They were born early because a medical decision was made that delivery was therapeutically necessary. In contrast, the con- trol babies who are preterm will be in that group either because of premature rupture of membranes or sponta- neous preterm labor. Causes of these two conditions, gener- ally not known, could possibly also be causes of CE Infection, for instance, involving the cervix, membranes, or placenta, might well be more common in babies bom preterm without exposure to PE than those with, and could well represent a risk factor for CPJ . 'Thus, as has been recently emphasized6. PE might not truly be protective, b u t only appear so in con- trast with the control babies who were delivered pretcrm for

Table I Relative risk of cerebral palsy in offspring of mothers with and without preeclampsia

~ ~ ~

' l k m or unylected neonates ! (iaffney et a[.' All PE 137 wk CP 2.0 (1 .2 .3 .4

severe PE CP 3.7(1.5,9.9) Palmer et 21." PI: All neonates CP N o effect Blair(' PE All neonates CP 1.6 (1.1,2.5) Dale and Stanley' PE All neondtcrs CP Significantly > 1 .O Nelson and Ellenberg" 'lijxcmia ' 2 5 7 g CP 1.7 (0.6,3.8)

I

Pretcm or low-binhweight neonates 'Topp et a1.5' . Maternal BP 5 36 wk with CP 2.4 (0.9.6.1)

2 140/90 ', BW C 2 SD for dA Nelson and Ellenberg') 'Toxemia 5 2500g CP 0.9 (0.2,2.5))

, Stanley and English" H I in pregnancy 5O1-20oO g CP No effect 1i'Tin pregnancy 2 2000g Hemiplegia. N o effect Powell ct 31.'" 'I)

ctiplegia j Murphyet al." PE <32 wk CP 0.6 (0.2.0.9) Nelson and GretherI2 PE < l5OOg CP 0.11 (0.01,2.-1) Schendcl er aI.*,' PE < l5oOg CP 0.35 (0.08, 1.43)

PE. preeclampsia; BW binhwcight; i IT, hypenension.

such reasons as infection. The only true control group with! whom we could compare the offspring of preeclamptic women would be elective preterm deliveries, but these (no doubt) do not exist in any numbers. In avahation of this bias,, PE could even appear protective when it actually was a direct cause of brain injury in the VLBW baby. Suppose some other factor (for instance, infection) was causative both of preterm delivery and o f a continuum of brain inju which allowed 1 for the survival of infants with disabilities. uppose that PE,

nism which was either lethal or which left '0 residual dam- age in survivors. Indeed, explorations of the intellectual abilities of the offspring of preeclamptics'k6 support the notion that there is no continuum of effect. The survivors of infection would include more children with Ck! and PE would appear protective when it was not trulyso. (b) IfGA is to be controlled for, it must be reliably assessed. But GA is less reliably assessed than is birthweight (BW), and the latter is therefore often substituted f& GA as the basis for defining at-risk cohorts or for statistical control. As PE is highly associ- ated with IUGR, a preeclamptic offspring in any weight cate- gory will likely be of greater GA than the corresponding LBW baby. Thus, if increasing GA protects against Cp PE may arti- factually appear protective". Even when GA is used for adjustment, cohorts without benefit of early antenatal ultra- sound may have GA determinations which are influenced by BW! In fact, even at present it is not inconceivable that the fre- quency with which an early ultrasound scan is obtained, or its reliability, might vary in relation to correlates of PE found

' in early pregnancy. (c) Iatrogenic termination of a preeclamptic pregnancy is a planned event. This termination generally occurs by either an abdominal delivery or by a care- ful, well-monitored vaginal delivery. In contrast, other preterm babies may have been through a vmety of more tumultuous labor, delivery, and postnatal experiences. If asphyxia during labor, the gentleness of the delivery process, or the availability of immediate neonatal care affect the risk of eventual Ce the preeclamptic mother's baby may derive protection from this greater opportunity for care. (2) The standard medical treatment for more severe forms of PE has forlmany years included use of magnesium sulfate. This in itself has been proposed as protective against CP Plausible

on the other hand, caused brain injury by a 1 ifferent mecha-

? .

mechanisms for such an effect have been describedAs. We and our colleague^^^^^^ have not reproduced this effect, and we share Blair et a1.k concernSo that the apparent protection may arise from the other biases listed above. But if magne- sium sulfate is protective, it.. use in preeclampsia would mi- factually make PE appear protective against CF? In contrast to the three biases listed earlier, this mechanism may apply to term pregnancies as well. (3) PE in its more severe and early-onset forms is commonly associated with IUGR. IUGR itselfhas been considered a significant risk factor for CPL6, yet recent information from Denmark5' has corroborated previous ~ ~ r k ~ ~ . ~ ~ indicating that this risk is confined to term or only moderately preterm babies. In the Danish spdy, IUGR was a risk factor for CP in babies wjth GA above 33 weeks, neutral in an intermediate group, and apparently protective in the small group of survivors below 30 weeks. It is plausible that wherever IUGR occurs, mechanisms could be set in place (such as an increase in adrenal corticosteroid release) which are protective against the developmentof CP in the preterm infant38. PE, as a marker of infants likely to be growth-retarded, would thus appear protective in the preterm group, while not actually directly so. In an interest- ing demonstration of many of these biases, a recent cohort of 745 consecutive neonates in New York StateJ3 with BW of 500 to 1750g were divided into three groups based upon whether their prematurity was physician-induced or the result of spontaneous preterm labor or premature rupture of membranes. Hypertensive complications of pregnancy and lUGR were the indication for 155 of the 181 iatrogenic preterm deliveries. The relative risk of major sonographic brain lesions for the iatrogenic group compared with the other two was 0.06 (0.01 to 0.19), and of any lesions was 0.38 (0.25 to 0.59). Compared with the other two groups,' the physician-initiated group had many fewer instances of clini- cal or histological chorioamnionitis, more IUGR, higher GA, and fewer low Apgar scores. Rates of abdominal delivery were not given, but can be expected co ha\T been higher when delivery was physician-induced.

Appropriate use of statistical procedures Explorations of the PEKP relation arc o@n reported with and/orr.without control for GA or BW without discussion of

Table II: Relative risk of ultrasound brain lesions in offspring of mothers with and without preeclampsia

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, Study : Erpsure Population Outcome Relative I definition risk

~~~~~ - ~~~~ ~

vande Boret al.'3 PE C1500gor PIVH 0.58 (0.35.0.95) GA < 32 wk

1.eviton et a1.1' 9 Toxemia 5 1500g GMH 0.14 (0.02,0.95) Kuban ct al.I5 PE C 1500g CMl1-IVH 0.14 (0.02, 1.0) O'Shea et al.I6 PE 650-1300g ., SEH-IVH 0.4(0.1,0.9) lmviton et Pregnancy-induced < 1500g PEA 0.38 (0.22.0.61)

hypertmsion IVH 0.38 (0.27,0.54) VMEC 0.25 (0.13,0.49)

PE, preeclampsia; PIVH. perivcntricular-intrventricular hemorrhage; GMH, germinal matrix hemorrhage; IVH, intraventricular hemorrhage; SEH. subependymal hemorrhage; PEA. parenchymal echo abnormality: VMEC, vcntriculomegaly.

Annotation 209

the conceptual meaning associated with these yrocedures. Controlling for GA is an attempt to ask: What is the direct effect of PE o n the risk of CP at every GA (that is, with <;A held constant)?

This is not, however, the only appropriate question. Since pregnancies are terminated'early due to treatment,' PE often alters the GA. And since being born preterm, whatever the reason, increases the risk of CP, then we must also be inter- ested in the indirect effect of PE upon CP risk, i.e the risk when GA is not held constant. We do the uncontrolled analy- sis first, which yields an overall measure of the risk associated with PE. That portion of the overall risk which is then abkrbed (decreased) by control for GAcan be interpreted as the risk contributed by PE which is mediated throqgh alter- ation of age of delivery. That which remains is a direct risk conferred by PE on infants ofjike GA.

Conclusions and recommendations It is probably not suprising that there is not yet a conclusive understanding of the relation of PE to Ct! given the difficul- ties in defining each of the two entities, the time necessary to be certain of CP, and the methodological difficulties outlined above. The recent much improved survival in preterm babies! heightens the need, however, to clarify the relation of PE and other potential risk factors to the potentially increasing bur- den of CP The opportunity for such study is improving, as sizeable cohorts of high-risk suniving preterm and VLBW infants now accumulate more quickly than before. Moreover, the advent of near-universal prenatal ultrasound examinations in many populations should result in much better definition of GA for each baby. We encourage the accu- mulation of more large population-based cohorts,' and of carcful attention to problems of study design and analysis.

The ' question originally posed by our hypothetical preeclamptic woman remains incompletely answered. The most precisc answer we could now give would be, 'Your preeclampsia may require that your baby be born early, and we do know that there is an increased likelihood of cerebral palsy. in premature babies. But if preterm delivery is neces- sary we would not expect your baby to have as high a risk as other preterm babies have, because his or her reason for being premature would be different.'

r

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z:8tL*.

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, Annotarion 2 1 1